We have explored how certain telomeric base lesions alter telomere integrity. Uracil in the genome can result from misincorporation of dUTP instead of dTTP during DNA synthesis, and is primarily removed by uracil DNA glycosylase (Ung) during base excision repair (BER). Telomeres contain long arrays of TTAGGG repeats and may be susceptible to uracil misincorporation. We have shown that uracil in telomeres weakens the binding by a key telomere binding protein, POT1, which may diminish POT1's ability to inhibit telomerase- or homologous recombination-mediated telomere length maintenance. To explore if uracil interferes with telomere length maintenance, we have examined highly proliferative mouse hematopoietic cells, either defective in Ung or cultured with folic acid depleted medium or anti-folate cancer therapeutic drugs, e.g. pemetrexed, that disrupt folate metabolism. All these conditions increase uracil loads at telomeres and lead to defective telomere length homeostasis. Our data underscore the necessity of Ung-initiated BER for the preservation of telomere length homeostasis in highly proliferative tissues or organs (Vallabhaneni V, et al., Defective repair of uracil causes telomere defects in mouse hematopoietic cells. J. Bio. Chem., 290:5502-11, 2015).